CN104140427A - Preparation method of tetrahydropyrazolo[1,5-a]pyridine - Google Patents
Preparation method of tetrahydropyrazolo[1,5-a]pyridine Download PDFInfo
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- CN104140427A CN104140427A CN201410317575.6A CN201410317575A CN104140427A CN 104140427 A CN104140427 A CN 104140427A CN 201410317575 A CN201410317575 A CN 201410317575A CN 104140427 A CN104140427 A CN 104140427A
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- Prior art keywords
- reaction
- pyrazoles
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- butyl carbamate
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- QQARYANIEPYVRK-UHFFFAOYSA-N Nc1ccn[n]1CCCBr Chemical compound Nc1ccn[n]1CCCBr QQARYANIEPYVRK-UHFFFAOYSA-N 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of tetrahydropyrazolo[1,5-a]pyridine, in particular to a preparation method of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine. A target product is obtained by performing Boc addition, nucleophilic substitution, Boc removal and nucleophilic substitution on 5-amino-1H-pyrazol serving as an initial raw material. A compound is an important medical intermediate.
Description
Technical field
The present invention relates to a kind of novel preparation method of medicine intermediate, special 4,5,6,7-tetrahydro-pyrazole is a kind of preparation method of [1,5-a] pyrimidine also.
Technical background
Compound 4,5,6,7-tetrahydro-pyrazole is [1,5-a] pyrimidine also, English 4,5,6,7-Tetrahydropyrazolo[1 by name, 5-a]-pyramidine, CAS:126352-69-0, structural formula is:
Antimicrobial agents is that current clinical application is wide, a class medicine of large usage quantity, aspect control and treatment disease, is playing an important role.The antimicrobial agents kind of current clinical use is numerous, but is widely used along with a large amount of of antimicrobial agents, particularly unreasonable application clinically, and even abuse, finally causes multidrug resistant.Therefore, how to overcome multidrug resistant and become the important topic of antimicrobial agents research both at home and abroad at present.The method that solves resistance is numerous, and wherein the research and development of novel texture antimicrobial agents are to solve one of important channel of resistance, have become the very active field of current pharmaceutical chemistry.
Pyrazolo [1,5-a] pyrimidine ring is a class basic group conventional in pharmaceutical chemistry research, and its toxicity is little, easily forms multiple hydrogen bonds or ionic linkage, often the lipid of regulating drug and acid base equilibrium constant effectively.Be introduced into molecule, can effectively increase the alkalescence of molecule and water-soluble, thereby strengthen the activity of molecule.Therefore, to a certain extent, piperazine group is a synergy group, in the design and development of many medicines of being everlasting, introduces.Research shows, often demonstrates biological activity widely containing the compound of pyrazolo [1,5-a] pyrimidine, as antimicrobial, hypertension, anticancer, anti-inflammatory and pain relieving etc., especially as antimicrobial agents, its research is active and development is rapid, demonstrates broad development potentiality.
The present invention relates to 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine has vital role for new drug development.
Summary of the invention
The invention discloses one and prepare the also method of [1,5-a] pyrimidine of 4,5,6,7-tetrahydro-pyrazole, taking 5-amino-1H-pyrazoles as starting raw material, in process, Boc, nucleophilic substitution, de-Boc, nucleophilic substitution obtain target product.Synthetic route as shown in Figure 1.Synthesis step is as follows:
(1), taking 5-amino-1H-pyrazoles as starting raw material, obtain 2 through amido protecting reaction;
(2) 2 and 1,3-dibromopropane generation nucleophilic reaction, obtain 3;
(3) take off Boc reaction 3 and obtain 4;
(3) carry out internal nucleophilic substitution 4 and obtain 5,
One preferred embodiment in, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate amino protecting group used is selected from tert-Butyl dicarbonate; Described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate alkali used and is selected from salt of wormwood; The reagent that described deaminizating protecting group is reacted used is selected from hydrogenchloride; Described nucleophilic reaction prepare 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine alkali used be selected from potassium hydroxide.
One preferred embodiment in, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate solvent used is selected from methylene dichloride; Described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate solvent used and is selected from tetrahydrofuran (THF); Deaminizating protecting group react used solvent and be selected from methylene dichloride; Described nucleophilic reaction prepare 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine solvent used be selected from toluene.
One preferred embodiment in, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate temperature of reaction used is room temperature; It is the reflux temperature of solvent that described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate temperature used; The temperature that described deaminizating protecting group is reacted used is 0 DEG C; It is the reflux temperature of solvent that described ring-closure reaction is prepared 2-(4-is to halogenophenyl) piperazine temperature used; Described nucleophilic reaction prepare 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine temperature used be the reflux temperature of solvent.
The present invention relates to one and prepare the also method of [1,5-a] pyrimidine of 4,5,6,7-tetrahydro-pyrazole, there is no at present other Patents bibliographical informations.
Brief description of the drawings
Fig. 1 is the also synthetic route chart of [1,5-a] pyrimidine of 4,5,6,7-tetrahydro-pyrazole.
The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is further limited.One skilled in the art will understand that the replacement that is equal to that technical characterictic of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) 1H-pyrazoles-5-t-butyl carbamate is synthetic
50g5-amino-1H-pyrazoles is joined in 600ml methylene dichloride, add 86g tert-Butyl dicarbonate, stirring at room temperature 12 hours, adds water to extract, separatory, dry, concentrated, and residuum upper prop separates and obtains 72g1H-pyrazoles-5-t-butyl carbamate.
(2) 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate is synthetic
70g1H-pyrazoles-5-t-butyl carbamate is joined in 500ml tetrahydrofuran (THF), add again 43g salt of wormwood, reflux 18 hours, be cooled to room temperature, add water and ethyl acetate, extraction separatory, collects organic phase again, separatory, dry, concentrated, on residuum, silicagel column separates to obtain 76g1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate.
(3) 1-(3-bromopropyl)-1H-pyrazoles-5-amine is synthetic
75g1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate is joined in 1000ml methylene dichloride, be cooled to 0 DEG C, pass into hydrogenchloride until saturated, stir 24 hours, add sodium bicarbonate aqueous solution, extraction separatory, collects organic phase, separatory, dry, concentrated, on residuum, silicagel column separates to obtain 48g1-(3-bromopropyl)-1H-pyrazoles-5-amine.
(4) 4,5,6,7-tetrahydro-pyrazole is synthesizing of [1,5-a] pyrimidine also
45g1-(3-bromopropyl)-1H-pyrazoles-5-amine is joined in 600ml toluene, then add 25g potassium hydroxide, reflux, stir 6 hours, add water and ethyl acetate, extraction separatory, collects organic phase, separatory, dry, concentrated, on residuum, silicagel column separates to obtain 18g4,5,6,7-tetrahydro-pyrazole is [1,5-a] pyrimidine also.
Claims (6)
1. prepare the also method of [1,5-a] pyrimidine of 4,5,6,7-tetrahydro-pyrazole for one kind, taking 5-amino-1H-pyrazoles as starting raw material, in process, Boc, nucleophilic substitution, de-Boc, nucleophilic substitution obtain target product 5, and synthetic route is as follows.
。
2. according to the method for claim 1,4 steps described in it is characterized by are reacted and are,
(1), taking 5-amino-1H-pyrazoles as starting raw material, obtain 2 through amido protecting reaction;
(2) 2 and 1,3-dibromopropane generation nucleophilic reaction, obtain 3;
(3) take off Boc reaction 3 and obtain 4;
(3) carry out internal nucleophilic substitution 4 and obtain 5,
。
3. according to the method for claim 1-2, it is characterized in that, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate amino protecting group used is selected from tert-Butyl dicarbonate; Described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate alkali used and is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; The reagent that described deaminizating protecting group is reacted used is selected from one or more the mixture in hydrochloric acid, hydrogenchloride, sulfuric acid, trifluoroacetic acid, tosic acid; Described nucleophilic reaction prepares 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine alkali used is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus.
4. according to the method for claim 1-2, it is characterized in that, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate solvent used is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate solvent used and is selected from methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene, tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; The solvent that described deaminizating protecting group is reacted used is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described nucleophilic reaction prepares 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine solvent used is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
5. according to the method for claim 1-2, it is characterized in that, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate temperature of reaction used is the reflux temperature of 0 DEG C~solvent; It is the reflux temperature of 0 DEG C~solvent that described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate temperature used; The temperature that described deaminizating protecting group is reacted used is 0 DEG C~room temperature; Described nucleophilic reaction prepare 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine temperature used be the reflux temperature of 0 DEG C~solvent.
6. according to the method for claim 1-2, it is characterized in that, described amido protecting reaction preparation 1H-pyrazoles-5-t-butyl carbamate temperature of reaction used is room temperature; It is the reflux temperature of solvent that described nucleophilic reaction is prepared 1-(3-bromopropyl)-1H-pyrazoles-5-t-butyl carbamate temperature used; The temperature that described deaminizating protecting group is reacted used is 0 DEG C; It is the reflux temperature of solvent that described ring-closure reaction is prepared 2-(4-is to halogenophenyl) piperazine temperature used; Described nucleophilic reaction prepare 4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine temperature used be the reflux temperature of solvent.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018104474A1 (en) | 2016-12-09 | 2018-06-14 | L'oreal | Compound derived from 4,5-diaminopyrazoles comprising a fused ring, composition comprising at least one such compound, implementation process and use |
CN110922409A (en) * | 2019-12-19 | 2020-03-27 | 武汉九州钰民医药科技有限公司 | Method for preparing BTK inhibitor zebritinib |
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CN1070404A (en) * | 1991-09-09 | 1993-03-31 | 藤泽药品工业株式会社 | New Hete rocyclic derivatives |
CN1075965A (en) * | 1992-03-02 | 1993-09-08 | 藤泽药品工业株式会社 | New Hete rocyclic derivatives |
CN1522259A (en) * | 2001-05-01 | 2004-08-18 | ����ҩƷ��ҵ��ʽ���� | Cephem compounds |
CN1675209A (en) * | 2002-08-07 | 2005-09-28 | 三菱制药株式会社 | Dihydropyrazolopyridine compounds |
EP1970373A1 (en) * | 2005-12-02 | 2008-09-17 | Mitsubishi Tanabe Pharma Corporation | Alicyclic heterocyclic compound |
CN101472917A (en) * | 2006-04-18 | 2009-07-01 | 阿斯利康(瑞典)有限公司 | Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands |
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- 2014-07-05 CN CN201410317575.6A patent/CN104140427A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1070404A (en) * | 1991-09-09 | 1993-03-31 | 藤泽药品工业株式会社 | New Hete rocyclic derivatives |
CN1075965A (en) * | 1992-03-02 | 1993-09-08 | 藤泽药品工业株式会社 | New Hete rocyclic derivatives |
CN1522259A (en) * | 2001-05-01 | 2004-08-18 | ����ҩƷ��ҵ��ʽ���� | Cephem compounds |
CN1675209A (en) * | 2002-08-07 | 2005-09-28 | 三菱制药株式会社 | Dihydropyrazolopyridine compounds |
EP1970373A1 (en) * | 2005-12-02 | 2008-09-17 | Mitsubishi Tanabe Pharma Corporation | Alicyclic heterocyclic compound |
CN101472917A (en) * | 2006-04-18 | 2009-07-01 | 阿斯利康(瑞典)有限公司 | Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018104474A1 (en) | 2016-12-09 | 2018-06-14 | L'oreal | Compound derived from 4,5-diaminopyrazoles comprising a fused ring, composition comprising at least one such compound, implementation process and use |
CN110922409A (en) * | 2019-12-19 | 2020-03-27 | 武汉九州钰民医药科技有限公司 | Method for preparing BTK inhibitor zebritinib |
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